The two major objectives of this program are: 1) to apply existing knowledge of human biochemistry and genetics to the preventive control and treatment of human hereditary diseases, and 2) to extend our understanding of normal and abnormal gene function in human cells at various levels of biological organization, ranging from the molecular and cellular level to that of the embryo, infant, child and adult patient. The cascading interaction of the different phases of the program will in turn generate answers to secondary goals of interest to both basic biomedical science and applied clinical medicine. The expression of specific enzyme defects of genetic origin in cultured human fibroblasts, lymphoblasts, or amniotic cells provides a very real physical bridge for eliciting a wide range of collaborative studies between clinicians and basic scientists. Such defects can serve as biochemical markers for studies of basic genetic mechanisms of mammalian cells. Likewise, the perturbation in normal cell function produced by an abnormal gene provides detailed insight into the secondary and tertiary effects of the normal gene product. The same biochemical or cytogenetic defects identified in fetal amniotic cells have opened a whole new field of preventive medicine for the control of over fifty serious and incapacitating hereditary diseases through prenatal diagnosis and selective management of gestation. Participants in this program come from the departments of Medicine, Pediatrics, Pathology, Biology, Obstetrics and Gynecology, Chemistry and Neurosciences and are experienced in application of technical disciplines including protein chemistry, enzymology, cell culture, virology, immunochemistry, neurochemistry, genetics, cytogenetics, and a variety of techniques involved in cell biology. The various research proposals show a substantial amount of interdigitation,and each major area will require the collaborative efforts of several principal participants who have chosen to work together in the expanded collaborative environment provided by the program.